雷帕霉素（everolimus）与丙草胺联用通过增强自噬作用协同诱导前列腺癌细胞凋亡。
Combination of Rad001 (everolimus) and propachlor synergistically induces apoptosis through enhanced autophagy in prostate cancer cells.
机构信息
Department of Urology and Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
出版信息
Mol Cancer Ther. 2012 Jun;11(6):1320-31. doi: 10.1158/1535-7163.MCT-11-0954. Epub 2012 Apr 5.
Abstract
PI3K/AKT/mTOR pathway plays a key role in the tumorigenesis of many human cancers including prostate cancer. However, inhibitors of this pathway, such as Rad001, have not shown therapeutic efficacy as a single agent. Through a high-throughput screen of 5,000 widely used small molecules, we identified compounds that can synergize with Rad001 to inhibit prostate cancer cells. One of the compounds, propachlor, synergizes with Rad001 to induce apoptosis of castration-resistant prostate cancer cells via enhanced autophagy. This enhanced autophagic cell death is accompanied by increased Beclin1 expression as well as upregulation of Atg5-Atg12 conjugate and LC3-2. Rad001 and propachlor can also synergistically inhibit tumors in a xenograft animal model of prostate cancer. These findings provide a novel direction to develop combination therapies for advanced and metastatic prostate cancer that has failed the currently available therapies.
摘要
PI3K/AKT/mTOR 通路在许多人类癌症的肿瘤发生中发挥着关键作用，包括前列腺癌。然而，该通路的抑制剂，如 Rad001，作为单一药物并未显示出治疗效果。通过对 5000 种广泛使用的小分子进行高通量筛选，我们发现了一些能够与 Rad001 协同抑制前列腺癌细胞的化合物。其中一种化合物丙泊酚可通过增强自噬与 Rad001 协同诱导去势抵抗性前列腺癌细胞凋亡。这种增强的自噬细胞死亡伴随着 Beclin1 表达的增加以及 Atg5-Atg12 缀合物和 LC3-2 的上调。Rad001 和丙泊酚还可以协同抑制前列腺癌异种移植动物模型中的肿瘤。这些发现为开发针对目前可用疗法失败的晚期和转移性前列腺癌的联合治疗提供了新的方向。
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